Comparison between 2-hydroxypropyl-β-cyclodextrin and 2-hydroxypropyl-γ-cyclodextrin for inclusion complex formation with danazol

Abstract

Complexation in solution between danazol and two different cyclodextrins [2-hydroxypropyl-β-cyclodextrin (HP-β-CD) and 2-hydroxypropyl-γ-cyclodextrin (HP-γ-CD)] was studied using phase solubility analysis, and one- and two-dimensional 1H-NMR. The increase of danazol solubility in the aqueous cyclodextrin solutions showed a linear relationship (AL profile). The apparent stability constant, K1:1, of each complex was calculated and found to be 51.7 × 103 and 7.3 × 103 M−1 for danazol–HP-β-CD and danazol–HP-γ-CD, respectively. 1H-NMR spectroscopic analysis of varying ratios of danazol and the different cyclodextrins in a mixture of EtOD–D2O confirmed the 1:1 stoichiometry. Cross-peaks, from 2D ROESY 1H-NMR spectra, between protons of danazol and H3′ and H5′of cyclodextrins, which stay inside the cyclodextrin cavity, proved the formation of an inclusion complex between danazol and the cyclodextrins. For HP-β-CD, the inclusion complex is formed by entrance of the isooxazole and the A rings of danazol in the cyclodextrin cavity. For HP-γ-CD, two different inclusion structures may exist simultaneously in solution: one with the isooxazole and A ring in the cavity and the other with the C and D ring inside the cavity. DLS showed that self-aggregation of the CD’s was absent in the danazol HP-β-CD system up to a CD concentration of 10% and in the danazol HP-γ-CD system up to a CD concentration of 5%.